Obituary

Paul C. Zamecnik (1912–2009)

Trailblazer in the study of protein synthesis.

Credit: MERCER PHOTOGRAPHY/UMASS MED. SCHOOL

In April 1940, as low-flying German planes dropped leaflets over Copenhagen announcing that Denmark was now occupied, a young American on a travelling fellowship at the Carlsberg Laboratories realized that he would have to leave. But that young man, Paul Zamecnik, had already absorbed much from the lab's director, the biochemist Kaj Linderstrøm-Lang. Back in the United States, Zamecnik's second try for a post with Max Bergmann at the Rockefeller Institute in New York City was successful, and in due course he took charge of his own group at the Massachusetts General Hospital in Boston. There he revolutionized the study of protein biosynthesis through the use of a cell-free (in vitro) system, thus revealing the enzymatic activation of amino acids, the ribosome as the site of peptide-bond formation and the existence of transfer RNA. Zamecnik died at his home in Boston on 27 October.

Zamecnik grew up in Cleveland, Ohio, and at 16 went to Dartmouth College in Hanover, New Hampshire. Graduation from Harvard Medical School in 1936 was followed by an internship back in Cleveland and then a residency at Mass General. His interest in research was apparent early on, as was a strong degree of self-determination. Indeed, even as a medical resident, Zamecnik travelled to New York City to seek a position with Bergmann, who replied that he took only organic chemists. But Zamecnik was prescient to try, for at the time this was virtually the only US laboratory working on protein synthesis.

In 1942, Zamecnik returned from the Rockefeller to Mass General, where, under the freedom granted by Joseph Aub, he collaborated on such projects as a study with Fritz Lipmann of the mechanism of α-toxin produced by Clostridium bacteria. But by now, Zamecnik was emerging as a scientific leader in his own right, and a magnet for talent. One to join him was Robert Loftfield. With the recent availability of a long-half-life radioisotope of carbon, Loftfield used the hydrogen-cyanide-based Strecker synthesis to produce the radiolabelled amino acid 14C-alanine. Employing a cell-free system, and with key contributions by Philip Siekevitz, Zamecnik's group obtained the first definitive data showing protein synthesis in a test tube, including compelling evidence that the labelled amino acid was located internally in the product chain. Soon Mahlon Hoagland joined Zamecnik's group, and using the same system discovered the enzymatic activation of amino acids via the formation of acyl anhydrides with adenylate, conceptually sparked by Hoagland's previous postdoc work with Lipmann, upstairs at Mass General.

While Hoagland was working on amino-acid activation, Zamecnik was puzzling over an odd observation in his own experiments. He had seen that 14C-ATP became covalently bound to endogenous RNA in his system, hinting that RNA synthesis might be occurring (this was well before the discovery of RNA polymerase, the enzyme now known to produce RNA). As a control, he had run a separate reaction with 14C-valine and observed that it too became attached to RNA before ending up in protein. Hoagland and others in the lab worked through this puzzle and discovered that a low-molecular-weight RNA fraction behaved as an intermediate in the movement of amino acids from their ATP-activated state into protein.

This was the discovery of transfer RNA, which had been brilliantly predicted by Francis Crick about two years earlier in a conference talk and an unpublished short manuscript that had not reached the Zamecnik group. Crick was said to be elated by the arrival of hard data, whereas Zamecnik had never considered trusting anything less.

In the 1960s, Zamecnik turned his attention to Rous sarcoma virus (RSV), the RNA genome of which is 'reverse transcribed' into DNA for virus replication. His lab started sequencing the region just inside one end, the 3′ end, of the genome. Across the Charles River, at Harvard's main campus, Walter Gilbert and Allan Maxam were sequencing in from the 5′ end using their faster method. The results were soon at hand in both camps — the sequences at both ends were the same, and had the same polarity. From this it became apparent that, during reverse transcription, the 5′ end of the DNA product strand would be complementary to the template RNA's 5′ end and might form a circle with it.

From this, Zamecnik astutely envisaged that blocking circularization might be an antiviral approach. He used a 13-base-long oligodeoxynucleotide complementary to the terminal repeats of RSV to inhibit the translation of viral messenger RNA in a cell-free system and, more momentously, in RSV-infected cells (Proc. Natl Acad. Sci. USA 75, 280–284, 285–288; 1978). These two papers by Zamecnik and M. L. Stephenson launched the era of antisense DNA, which became widely adopted as a powerful tool for experimentally silencing gene expression, almost two decades before the advent of gene silencing by exogenous small interfering RNAs. Meanwhile, commercial efforts began (and continue) to move antisense DNA into clinical application.

Zamecnik's many honours included the US National Medal of Science in 1991 and, in 1996, only the second Albert Lasker Award for Special Achievement in Medical Science to be conferred. Shakespeare (whom Zamecnik could quote extensively from memory) wrote in Hamlet:“What a piece of work is a man ... how express and admirable!” Zamecnik was express: he was supremely articulate, and also in a hurry (but too much the gentleman to ever show it). And he was admirable: he always attracted crowds at scientific or social events, not least because of his talent as a storyteller; and as a colleague of his for many years, I often saw him conversing with janitors and other 'sub-faculty' staff, by whom he was held in the same high regard as he was by his scientific peers. He was a most likeable man, a lab-bench perfectionist, and a high-affinity group leader. Medicine, at least on the wards, was not for him, and molecular biology has been the better for that.

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Pederson, T. Paul C. Zamecnik (1912–2009). Nature 462, 423 (2009). https://doi.org/10.1038/462423a

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